Neurocognitive Functions After 6-Month Buprenorphine (Naloxone)-Based Opioid Agonist Maintenance Treatment: A Controlled Prospective Study.

BACKGROUND: Medications for opioid use disorder (OUD) may influence neurocognitive functions. Inadequate power, confounders, and practice effects limit the validity of the existing research. We examined the change in cognitive functions in patients with OUD at 6-month buprenorphine (naloxone) posttreatment and compared the cognitive performance of the buprenorphine-treated group with control subjects. METHODS: We recruited 498 patients with OUD within a week of initiating buprenorphine. Assessments were done twice-at baseline and 6 months. Those abstinent from illicit opioids and adherent to treatment (n = 199) underwent follow-up assessments. Ninety-eight non-substance-using control subjects were recruited from the community. The neurocognitive assessments comprised the Wisconsin Card Sorting Test, Iowa Gambling Task, Trail-Making Tests A and B (TMT-A and TMT-B), and verbal and visual N-Back Test. We controlled for potential effect modifiers. RESULTS: Twenty-five of the 32 test parameters significantly improved with 6 months of buprenorphine treatment; 20 parameters withstood corrections for multiple comparisons (P < 0.001). The improved test domains spread across cognitive tests: Wisconsin Card Sorting Test (perseverative errors and response, categories completed, conceptual responses), TMTs (time to complete), verbal and visual N-Back Tests (hits, omission, and total errors). After treatment, OUD (vs control subjects) had less perseverative response and error (P < 0.001) and higher conceptual response (P = 0.004) and took lesser time to complete TMT-A (P < 0.001) and TMT-B (P = 0.005). The baseline neurocognitive functions did not differ between those who retained and those who discontinued the treatment. CONCLUSION: Cognitive functions improve in patients with OUD on buprenorphine. This improvement is unlikely to be accounted for by the practice effect, selective attrition, and potential confounders.

The Neuro-Ophthalmology of Tuberculosis.

Tuberculosis (TB) is a global health concern and central nervous system (CNS) TB leads to high mortality and morbidity. CNS TB can manifest as tubercular meningitis, tuberculoma, myelitis, and arachnoiditis. Neuro-ophthalmological involvement by TB can lead to permanent blindness, ocular nerve palsies and gaze restriction. Visual impairment is a dreaded complication of tubercular meningitis (TBM), which can result from visual pathway involvement at different levels with varying pathogenesis. Efferent pathway involvement includes cranial nerve palsies and disorders of gaze. The purpose of this review is to outline the various neuro-ophthalmological manifestations of TB along with a description of their unique pathogenesis and management. Optochiasmatic arachnoiditis and tuberculomas are the most common causes of vision loss followed by chronic papilloedema. Abducens nerve palsy is the most commonly seen ocular nerve palsy in TBM. Gaze palsies with deficits in saccades and pursuits can occur due to brainstem tuberculomas. Corticosteroids are the cornerstone in the management of paradoxical reactions, but other immunomodulators such as thalidomide and infliximab are being explored. Toxic optic neuropathy caused by ethambutol necessitates careful monitoring and immediate drug discontinuation. Cerebrospinal fluid diversion through ventriculo-peritoneal shunting may be required in patients with hydrocephalus in stage I and II of TBM to prevent visual impairment. Early diagnosis and prompt management are crucial to prevent permanent disability. Prevention strategies, public health initiatives, regular follow-up and timely intervention are essential in reducing the burden of CNS TB and its neuro-ophthalmological complications.

MR vessel wall imaging in cerebral bacterial and fungal infections.

PURPOSE: Central nervous system (CNS) bacterial and fungal infections can cause secondary vasculitis which worsens the prognosis due to development of complications like infarctions or hemorrhages. In this prospective study, we aim to study intracranial vessel wall imaging findings in bacterial and fungal infections. METHODS: We included 12 cases of nontubercular bacterial and fungal CNS infections each, in whom definitive microbiological diagnosis could be made. High-resolution vessel wall imaging (VWI) and time of flight MR angiography (TOF MRA) were incorporated in the routine imaging protocol. All cases were evaluated for the presence of vascular enhancement, pattern of enhancement, and stenosis on VWI. Statistical analysis was done to evaluate association between findings of vessel wall imaging and infarctions. RESULTS: We found infarctions in 5 out of 12 cases (41.7%) of the bacterial group and 7 out of 12 cases (58.3%) of the fungal group. Vessel wall enhancement was seen in 5 cases (41.7%) of the bacterial group and 9 cases (75%) of the fungal group. There was a significant association between infarctions and vessel wall enhancement in the fungal group. However, pattern of enhancement or stenosis on VWI was not significantly associated with presence of infarction. VWI detected more cases of vascular involvement than TOF MRA. CONCLUSION: Secondary infectious vasculitis in bacterial and fungal infections can be detected by VWI, which can play an important role in better patient management as detection of vascular involvement can prompt early treatment to prevent complications like infarctions or hemorrhages.

High-resolution intracranial vessel wall imaging in cerebral viral infections evaluations.

PURPOSE: Vascular complications can be seen in various viral CNS infections. Variable neuro-imaging findings have been described in the literature elucidating the parenchymal changes with vascular involvement. Vessel wall imaging (VWI) can help to detect these vascular involvements. We aimed to describe the role and usefulness of VWI in the evaluation of various viral CNS infections. METHODS: In this prospective study, we included 15 cases of various diagnosed viral CNS infections (varicella, HIV encephalopathy, HSV encephalitis, Japanese encephalitis, dengue, COVID-19). VWI and time-of-flight MR angiography (TOF MRA) were included in imaging protocol. All cases were evaluated for the presence of cerebral parenchymal changes, vascular enhancement, and vascular stenosis. RESULTS: We found infarctions in all 5 cases of varicella, 1 case of HIV encephalopathy, and 1 case of COVID-19 encephalopathy. All these cases also showed vascular enhancement and stenosis on VWI. The rest of the cases, including 1 case of HIV encephalopathy, 3 cases of herpes encephalitis, 2 cases of dengue, and 2 cases of Japanese encephalitis did not have any vascular complication, and also did not show vascular enhancement or stenosis. CONCLUSION: VWI can be useful in the detection of vascular involvement in various viral infections of CNS which show a relatively higher cerebrovascular complication rate like varicella, HIV encephalopathy, and COVID-19. However, VWI may not be useful in the routine evaluation of other viral infections like herpes, dengue, and Japanese encephalitis, which have a very low rate of cerebrovascular complication rate.

Carbamazepine versus levetiracetam in epilepsy due to neurocysticercosis.

BACKGROUND: The choice of antiepileptic drug (AED) in newly diagnosed neurocysticercosis (NCC) patients with epilepsy continues to be arbitrary. We compared efficacy and side effect profile of levetiracetam (LEV) and carbamazepine (CBZ) for the treatment of seizures in newly diagnosed patients with NCC. PATIENTS AND METHODS: This was an open-labeled randomized comparative monotherapy study including newly diagnosed drug naïve patients of NCC (n = 99) presenting with seizures who were randomized in 1:1 ratio using computed generated numbers. All patients were followed up for at least six months after start of treatment. The primary outcome measure was seizure control over six months following start of AEDs. RESULTS: Fifteen (15.2%) patients [CBZ- 4(8.2%); LEV- 11(22%)] developed recurrence of seizures. A trend (p = 0.09) was found toward better control of seizures in CBZ compared to LEV. Two (4%) patients in LEV group and 17 (34.6%) patients in CBZ group developed drug-related minor side effects (p < 0.0001). Three patients in CBZ group needed discontinuation of therapy due to skin rash. Eleven patients who relapsed while on LEV did not have any recurrence of seizures after switching over to CBZ. Out of 3 patients who relapsed while receiving CBZ and were changed to LEV, two developed seizures during follow-up. CONCLUSION: CBZ and LEV could be used as alternatives in newly diagnosed patients of NCC at the behest of minor side effects in the CBZ group.

MR vessel wall imaging in tubercular meningitis.

PURPOSE: Tubercular meningitis (TBM) has the propensity to cause secondary vasculitis through various mechanisms leading to development of cerebrovascular complications. These vascular involvements can be detected by vessel wall imaging (VWI). In this study, we aimed to study detailed findings of vessel wall imaging in cases of tubercular meningitis. METHODS: All consecutive patients of suspected tubercular meningitis in whom diagnosis of TBM could be made according to diagnostic criteria given by Ahuja et al. were included in the study. High-resolution MR VWI and time of flight (TOF) magnetic resonance angiography (MRA) were done along with routine MRI sequences. Arteries up to second-order branches were studied, and statistical analyses were done with respect to stage of tubercular meningitis, infarctions and TOF MRA findings. RESULTS: Out of all 101 cases of TBM, infarctions were found in 49 cases (48.5%), and vessel wall enhancement was seen in 67 cases (66.3%). With increasing severity of disease, more severe vascular involvement was seen on VWI. There was significant association between enhancement of individual arteries and infarctions in their territories. VWI had better sensitivity than the MRA, while MRA had better specificity than VWI for detection of vascular complications. CONCLUSION: Tubercular vasculitis can be detected by VWI in the form of nodular or smooth segmental enhancement of vessel wall with or without stenosis. Incorporation of VWI in routine MR imaging can play a greater role in early detection and management of cerebrovascular complications which can help to improve prognosis of the disease.

Magnetic bead flocculation test: Improving the diagnosis of tuberculous meningitis (TBM) in low-resource settings.

BACKGROUND: Despite several recent advances in detection techniques, there is still an unmet need for simple tests for the diagnosis of tuberculous meningitis (TBM). Therefore, in an effort towards developing a simple and rapid diagnostic test for resource-poor settings, we designed an assay in which magnetic bead flocculation test (MBF) was used to detect the amplified DNA. Multi-targeted (using two multicopy gene targets IS6110 and IS1081) loop-mediated isothermal amplification (MLAMP) was used for amplification. METHODS: MLAMP-MBF assay was performed on CSF samples of 600 patients, out of which 120 were definite TBM (culture confirmed), 280 were probable TBM and 200 were non-TB controls, based on Marais's criteria. The performance of assay was evaluated by comparing the result of definite TBM with culture and that of probable TBM with composite reference standard consisting of clinical, microbiological(smear/culture) and radiological parameters. RESULTS: The overall sensitivity of MLAMP-MBF (using any of the two gene targets) was 89.5% and specificity was 100%. The sensitivity was 96.6% (116/120) in diagnosing definite TBM and 86.4% (242/280) in diagnosing probable TBM. The sensitivity of IS1081 was 88% and that of IS6110 was 83% in diagnosing TBM. Specificity of both the gene targets was 100%. There were 20 cases positive only by IS1081 LAMP and 6 cases positive only by IS6110; thus 26 of 400 (6.5%) TBM cases could be additionally detected following multi-targeted approach. CONCLUSION: MLAMP-MBF is a sensitive, robust, cost-effective and promising technique for diagnosis of TBM in low-resource high-endemic settings.

Screening for paroxysmal nocturnal hemoglobinuria (PNH) in patients presenting with cerebral sinovenous thrombosis (CSVT): Results of a FLAER based flowcytometry study in Indian patients.

Patients with paroxysmal nocturnal hemoglobinuria (PNH) may present with thrombosis at unusual sites, of which cerebral sinovenous thrombosis (CSVT) is one and screening for PNH is recommended in this condition. Though many patients diagnosed with PNH develop CSVT, it is unclear how many patients with PNH would present for the first time with thrombosis. We analysed the results of screening for PNH by flowcytometry in our patients with CSVT. The laboratory data of patients referred for thrombophilia and PNH testing in CSVT was examined to assess the frequency of PNH at presentation in these patients. FLAER and CD24 on granulocytes and FLAER and CD14 on monocytes respectively were used to screen the leucocytes for PNH by flowcytometry. The data for Protein C, S and Antithrombin deficiency, antiphospholipid antibodies and the Factor V Leiden mutation was examined and circumstantial risk factors were also assessed. Of the 180 cases of CSVT screened by flowcytometry for PNH, not a single case tested positive. Positivity for anti-phospholipid antibodies was the most common thrombophilic risk factor (5%). Pregnancy was the most common circumstantial risk factor. Our data on FLAER based flowcytometry in the North Indian population with CSVT suggests that PNH is not a common risk factor in our patients with thrombosis at this unusual site.

Neurokinin 3 Receptor Antagonism: A Novel Treatment for Menopausal Hot Flushes.

Menopause is associated with significant symptomatic burden, with approximately two-thirds of postmenopausal women suffering from vasomotor symptoms, hot flushes, and night sweats. The mainstay of treatment for hot flushes continues to be hormone replacement therapy. However, as hormone replacement therapy is contraindicated in some cases, alternative, efficacious treatment options are also required. Hot flushes are thought to arise as a result of significant changes in the neuroendocrine circuitry underpinning the reproductive axis during menopause. This includes reduced circulating ovarian oestrogens, hypersecretion of gonadotropins, and increased expression of kisspeptin and neurokinin B (NKB) within the infundibular nucleus of the hypothalamus. In recent years, NKB, predominantly acting via the neurokinin 3 receptor (NK3R), has emerged as an important player in the development of menopausal hot flushes. Antagonism of NK3R has garnered much interest as a novel therapeutic target to help ameliorate hot flush symptoms. Improvements in hot flush frequency, severity, and quality of life have been demonstrated in a number of clinical trials using novel NK3R antagonists in postmenopausal women. Within this review, we will explore the growing body of evidence supporting antagonism of NK3R as a potentially promising treatment for menopausal hot flushes.

In-silico analysis of novel p.(Gly14Ser) variant of ATOX1 gene: plausible role in modulating ATOX1-ATP7B interaction.

Clinical heterogeneity is commonly observed in Wilson disease (WD), including cases with identical ATP7B mutations. It is thought to be an outcome of impairment in other genes involved in cellular copper homeostasis in addition to the mutations in the ATP7B gene. ATOX1, a copper chaperone that delivers copper to ATP7B, is a potential genetic modifier of WD. In the present study, we analyzed the genetic variations in the ATOX1 gene in 50 WD patients and 60 controls. We identified four novel variants, of which, the coding region variant c.40G > A, p.(Gly14Ser) was observed in 2% alleles. Interestingly, p.(Gly14Ser) was seen with an early onset age, reduced serum ceruloplasmin level and manifestations of liver and brain in a WD patient unlike the other having identical ATP7B mutation but normal ATOX1 alleles. Further, computational analysis predicted that p.(Gly14Ser) substitution, in the critical copper binding motif (MXCXG14C) of the protein, affects the protein-protein interaction involved in copper sharing and transfer between ATOX1 and ATP7B-MBD4. Our findings suggest that p.(Gly14Ser) variant of ATOX1 might play a role as a genetic modifier leading to phenotypic variation in WD.

Characterization of mutation spectrum and identification of novel mutations in ATP7B gene from a cohort of Wilson disease patients: Functional and therapeutic implications.

Wilson disease (WD), a copper metabolism disorder, occurs due to the presence of mutations in the gene encoding ATP7B, a protein that primarily facilitates hepatic copper excretion. A better understanding of spectrum and functional significance of ATP7B variants is critical to formulating targeted and personalized therapies. Henceforth, we screened and sequenced 21 exons of ATP7B gene from 50 WD patients and 60 healthy subjects. We identified 28 variants comprising, seven novels in 20% alleles, while eight variations affecting 23% alleles were first time reported in Indian cohort. The c.813C>A, p.(Cys271*) (10%) was the most frequent mutation. Bioinformatics analysis revealed five of seven novel variants viz. c.1600C>A, p.(Pro534Thr); c.1616C>A, p.(Pro539His); c.1924G>T, p.(Asp642Tyr); c.2168G>C, p.(Arg723Thr); c.2174G>C, p.(Arg725Thr) resulted in protein misfolding. Sequence conservation analysis of ATP7B regions containing novel variants documented an evolutionarily conserved nature. Functional analysis of these novel variants in five different cell lines lacking inherent ATP7B expression demonstrated sensitivity to CuCl2 -treatment, experiencing augmented cellular copper retention and decreased copper excretion as well as ceruloplasmin secretion to that of wildtype-ATP7B expressing cells. Interestingly, pharmacological chaperone 4-phenylbutyrate, a clinically approved compound, partially restored protein function of ATP7B mutants. These findings might enable novel treatment strategies in WD by clinically enhancing the protein expression of mutant ATP7B with residual copper export activity.

Cost-minimization analysis in the Indian subcontinent for treating Guillain Barre Syndrome patients with therapeutic plasma exchange as compared to intravenous immunoglobulin.

BACKGROUND: Therapeutic Plasma Exchange (TPE) and Intravenous Immunoglobulin both are first-line treatments for Guillain Barre Syndrome; however, there is a significant difference in cost. We undertook this study to assess the cost minimization for treating Guillain Barre Syndrome patients. METHODS: A prospective randomized controlled trial was undertaken, in which 40 Guillain Barre Syndrome (GBS) patients with a GBS disability score of grade four and five were enrolled. A societal perspective was adopted for the analysis and assessment of both the health system cost and out-of-pocket expenditures. Cost-minimization analysis was undertaken as both the treatments were equally effective at the end of 12 weeks. RESULTS: No statistically significant differences were observed in the GBS Disability scores during overall treatment course in both treatment groups. The Out-of-pocket cost for the immunoglobulin (IVIG) group was INR 219 247 (4298 USD) and for the TPE group was INR 104 070 (2040.5 USD). Overall INR 86 685 ($1700), that is, 53% higher cost was observed in IVIG group without any concomitant health outcome benefit. CONCLUSION: In comparison with IVIG, TPE appears to be the better option for treatment of GBS in cost-constraint countries like ours to provide an economic treatment option to most average people.

Surgery for post-traumatic facial paralysis: are we overdoing it?

PURPOSE: Early facial nerve decompression is recommended for cases of post-traumatic facial palsy on the basis of ENoG with degeneration > 95%. There is still a dispute in the literature concerning the role and timing of surgery versus conservative treatment in such cases. This study has been planned to evaluate the outcome of conservative management in traumatic facial paralysis with regard to type of trauma, onset, and electrodiagnostic tests. METHODS: A prospective cohort study included 39 patients with post-traumatic facial palsy. All patients underwent ENoG, nerve stimulation test, HRCT temporal bone and Schirmer's test. The patients received intravenous methylprednisolone 1 gm/day for 5 days or oral prednisolone 1 mg/kg in tapering doses for 3 weeks. Follow-up was done at 4, 12 and 24 weeks after the treatment. Surgical exploration was limited to patients showing no improvement after 12 weeks. Facial nerve function was evaluated by the HBFNS and FEMA grading systems. RESULTS: Among the 39 patients in the study [5 women and 34 men; mean (SD) age, 33.5 (11.37) years], facial nerve recovery with conservative treatment alone was noted in 31 patients. The first signs of clinical recovery were noted in 27 patients by 4 weeks, in 31 patients by 12 weeks. Seven patients required surgical exploration. At 24 weeks, 31 patients recovered to House-Brackmann grade I/III and 1 patient to grade IV. 19 of 26 patients with longitudinal fractures had grade I/III recovery, whereas all 6 patients with transverse fracture recovered on conservative treatment. CONCLUSIONS: Patients with incomplete facial palsy are candidates for conservative management. It is justified to try conservative management in patients with complete facial paralysis for up to 3 months even in cases where ENoG and NET suggest poor prognosis. The presence of sensorineural hearing loss or transverse fracture at presentation does not suggest a poor prognosis for improvement.

A mechanistic approach to explore the neuroprotective potential of zonisamide in seizures.

BACKGROUND: Epilepsy, a disease of the brain, is one of the most common serious neurological conditions. It is associated with a group of processes which alter energy metabolism, interrupt cellular ionic homeostasis, cause receptor dysfunction, activate inflammatory cascade, alter neurotransmitter uptake and result in neuronal damage. The increasing knowledge and understanding about the basis of neuronal changes in epilepsy lead to investigate the mechanistic pathway of neuroprotective agents in epilepsy. With this background, the present study is designed to reveal the molecular and biochemical mechanisms involved in the neuroprotective potential of zonisamide in epilepsy. METHODS: Seizure-induced neuronal damage was produced by maximal electroshock seizures in animals. The oxidative stress and neuroinflammatory and apoptotic markers were assessed in the brain tissue of animals. RESULTS AND DISCUSSION: The present findings revealed that zonisamide treatment prevented the development of seizures in animals. Seizures-induced free radicals production and neuroinflammation were markedly ameliorated by zonisamide administration. In conclusion, the present study demonstrated the mechanisms behind the strong neuroprotective potential of zonisamide against seizures by attenuating the oxidative stress, inflammatory cascade and neuronal death associated with progression of seizures. It can be further developed as a neuroprotective agent for epilepsy and other neurodegenerative disorders.

Tuberculous meningitis: Challenges in diagnosis and management: Lessons learnt from Prof. Dastur's article published in 1970.

It has been approximately five decades since Dastur et al., published their seminal work on pathology of tuberculous meningitis (TBM). Though most of their findings find relevance in today's era, there is an important difference; these findings can now be replicated during life using modern day technology. In this article, we review the seminal words of Professor Dastur and colleagues, analyse their findings, interpret how these revolutionized our understanding of TBM and highlight their relevance in today's era. We also discuss challenges in the management of TBM, which we continue to face today and the various options required to overcome these challenges.

The Eye Opener: Finding and Targeting the Midbrain Lesion.

Lesions of the central nucleus of the third cranial nerve in midbrain leads to bilateral ptosis. We present a case of a 14 year old boy, who was found to have B/L non-correctable ptosis and medial rectus palsy. There was a ring enhancing lesion in the midbrain in contrast MRI which resolved with treatment. The case exemplifies that bilateral ptosis results from the central nucleus involvement of third nerve which has bilateral innervation.

Comparison of ropivacaine (0.2%) with or without clonidine 1 µg/kg for epidural labor analgesia: A randomized controlled study.

BACKGROUND AND AIMS: The aim is to determine the effect of addition of clonidine to ropivacaine for epidural labor analgesia with regard to onset of analgesia, duration of analgesia, neonatal outcome, and quality of analgesia. MATERIAL AND METHODS: A total of 60 term parturients of the American Society of Anesthesiologists Grade I and II with uncomplicated pregnancy, vertex presentation, posted for on-demand epidural labor analgesia after informed consent were divided in two groups. Group R (n = 30) patients received 10 ml solution comprising 0.2% ropivacaine. Group RC (n = 30) patients received a total of 10 ml of 0.2% ropivacaine and clonidine 1 µg/kg. Characteristics of the block, onset and duration of analgesia, and total analgesic requirements were noted. Pain and overall satisfaction scores were assessed with a 10-point visual analog scale. Mode of delivery and neonatal APGAR scores were recorded. RESULTS: Maternal demographic characteristics were comparable between the groups. Addition of clonidine to ropivacaine shortened the onset and prolonged the duration of analgesia with decrease in ropivacaine requirement in Group RC. There was a significant difference between the two groups regarding visual analog score and quality of analgesia, which was better in Group RC. There were no significant differences between the two groups regarding motor block, hemodynamic parameters, and neonatal outcomes. CONCLUSION: We conclude that clonidine in low doses is a useful adjuvant to local anesthetics for epidural labor analgesia and a good alternative to opioids.

Linezolid Induced Reversible Peripheral Neuropathy.

Linezolid has been increasingly used for several severe infections including multidrug-resistant tuberculosis. Peripheral neuropathy is a rare side effect of linezolid and is conventionally considered as irreversible. Here, we report a case of reversible neuropathy induced by linezolid.

The dilemma of arranged marriages in people with epilepsy. An expert group appraisal.

INTRODUCTION: Matrimony remains a challenging psychosocial problem confronting people with epilepsy (PWE). People with epilepsy are less likely to marry; however, their marital prospects are most seriously compromised in arranged marriages. AIMS: The aim of this study was to document marital prospects and outcomes in PWE going through arranged marriage and to propose optimal practices for counseling PWE contemplating arranged marriage. METHODS: A MEDLINE search and literature review were conducted, followed by a cross-disciplinary meeting of experts to generate consensus. RESULTS: People with epilepsy experience high levels of felt and enacted stigma in arranged marriages, but the repercussions are heavily biased against women. Hiding epilepsy is common during marital negotiations but may be associated with poor medication adherence, reduced physician visits, and poor marital outcome. Although divorce rates are generally insubstantial in PWE, divorce rates appear to be higher in PWE undergoing arranged marriages. In these marriages, hiding epilepsy during marital negotiations is a risk factor for divorce. CONCLUSIONS: In communities in which arranged marriages are common, physicians caring for PWE are best-equipped to counsel them about their marital prospects. Marital plans and aspirations should be discussed with the family of the person with epilepsy in a timely and proactive manner. The benefits of disclosing epilepsy during marital negotiations should be underscored.

Six months therapy for tuberculous meningitis.

BACKGROUND: Tuberculous meningitis (TBM) is the main form of tuberculosis that affects the central nervous system and is associated with high rates of death and disability. Most international guidelines recommend longer antituberculous treatment (ATT) regimens for TBM than for pulmonary tuberculosis disease to prevent relapse. However, longer regimens are associated with poor adherence, which could contribute to increased relapse, development of drug resistance, and increased costs to patients and healthcare systems. OBJECTIVES: To compare the effects of short-course (six months) regimens versus prolonged-course regimens for people with tuberculous meningitis (TBM). SEARCH METHODS: We searched the following databases up to 31 March 2016: the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; MEDLINE; EMBASE; LILACS; INDMED; and the South Asian Database of Controlled Clinical Trials. We searched the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) and ClinicalTrials.gov for ongoing trials. We also checked article reference lists and contacted researchers in the field. SELECTION CRITERIA: We included randomized controlled trials (RCTs) and prospective cohort studies of adults and children with TBM treated with antituberculous regimens that included rifampicin for six months or longer than six months. The primary outcome was relapse, and included studies required a minimum of six months follow-up after completion of treatment. DATA COLLECTION AND ANALYSIS: Two review authors (SJ and HR) independently assessed the literature search results for eligibility, and performed data extraction and 'Risk of bias' assessments of the included studies. We contacted study authors for additional information when necessary. Most data came from single arm cohort studies without a direct comparison so we pooled the findings for each group of cohorts and presented them separately using a complete-case analysis. We assessed the quality of the evidence narratively, as using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was inappropriate with no direct comparisons between short- and prolonged-course regimens. MAIN RESULTS: Four RCTs and 12 prospective cohort studies met our inclusion criteria, and included a total of 1881 participants with TBM. None of the included RCTs directly compared six months versus longer regimens, so we analysed all data as individual cohorts to obtain relapse rates in each set of cohorts.We included seven cohorts of participants treated for six months, with a total of 458 participants. Three studies were conducted in Thailand, two in South Africa, and one each in Ecuador and Papua New Guinea between the 1980s and 2009. We included 12 cohorts of participants treated for longer than six months (ranging from eight to 16 months), with a total of 1423 participants. Four studies were conducted in India, three in Thailand and one each in China, South Africa, Romania, Turkey and Vietnam, between the late 1970s and 2011.The proportion of participants classified as having stage III disease (severe) was higher in the cohorts treated for six months (33.2% versus 16.9%), but the proportion with known concurrent HIV was higher in the cohorts treated for longer (0/458 versus 122/1423). Although there were variations in the treatment regimens, most cohorts received isoniazid, rifampicin, and pyrazinamide during the intensive phase.Investigators achieved follow-up beyond 18 months after completing treatment in three out of the seven cohorts treated for six months, and five out of the 12 cohorts treated for eight to 16 months. All studies had potential sources of bias in their estimation of the relapse rate, and comparisons between the cohorts could be confounded.Relapse was an uncommon event across both groups of cohorts (3/369 (0.8%) with six months treatment versus 7/915 (0.8%) with longer), with only one death attributed to relapse in each group.Overall, the proportion of participants who died was higher in the cohorts treated for longer than six months (447/1423 (31.4%) versus 58/458 (12.7%)). However, most deaths occurred during the first six months in both treatment cohorts, which suggested that the difference in death rate was not directly related to duration of ATT but was due to confounding. Clinical cure was higher in the group of cohorts treated for six months (408/458 (89.1%) versus longer than six months (984/1336 (73.7%)), consistent with the observations for deaths.Few participants defaulted from treatment with six months treatment (4/370 (1.1%)) versus longer treatment (8/355 (2.3%)), and adherence was not well reported. AUTHORS' CONCLUSIONS: In all cohorts most deaths occurred in the first six months; and relapse was uncommon in all participants irrespective of the regimen. Further inferences are probably inappropriate given this is observational data and confounding is likely. These data are almost all from participants who are HIV-negative, and thus the inferences will not apply to the efficacy and safety of the six months regimens in HIV-positive people. Well-designed RCTs, or large prospective cohort studies, comparing six months with longer treatment regimens with long follow-up periods established at initiation of ATT are needed to resolve the uncertainty regarding the safety and efficacy of six months regimens for TBM.